Protein kinase enzymes constitute a large class of enzymes that catalyze the transfer of a phosphate group to a hydroxyl group located on a protein substrate. Aberrant expression of protein kinases has been shown to lead to uncontrolled cell proliferation, to disorders including bone diseases, metabolic diseases, inflammatory disorders, infectious diseases and disorders of the central nervous system.
A non complete list of kinases includes abl, ATK, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK5, CDK6, cRaf1, CSFIR, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, GSK-3, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PKA, PYK2, ros, tie1, tie2, TRK, Yes, Zap70.
Activation of cyclin-dependent kinases, hereinafter referred to as CDK, is involved in the control of progression of eukaryotic cells through their cell cycle. Namely, some members of this class, such as CDK1 (also known as CDC2, CDK2 and CDK4), are responsible for the initial commitment to the cell cycle entry from the resting state and to the ordered progression through the cycle phases. The loss or alteration of control in CDK regulation is an attractive target in cancer therapy and the inhibition of one or more CDKs could therefore offer a treatment for a variety of cancers.
Activation of glycogen synthase kinase 3, hereinafter referred to as GSK-3 in two isoforms, is involved in the control of several biological pathways, including the synthesis of glycogen. Its inhibition in disease states associated with elevated GSK-3 activity could produce useful compounds for the treatment, inter alia, of non-insulin dependent diabetes mellitus, acute stroke and other neurotraumatic injuries.
Activation of Ca2+/phospholipid-dependent protein kinases, hereinafter referred to as PKC in ten isoforms, is involved in the mediation of cellular responses to extracellular stimuli intertwined with proliferation, differentiation and apoptosis, and also in the regulation of neurotransmitter release. Its inhibition in disease states associated with elevated PKC activity could produce useful compounds for the treatment, inter alia, of diabetes mellitus and as chemotherapeutics for the treatment of various malignant diseases.
Activation of the mitogen-activated protein kinases, hereinafter referred to as MAPK family is involved in important cellular regulation events related with tumor therapy, central nervous system disorders and inflammatory disorders. Inhibition of one or more MAPKs involved in a specific signaling pathways could therefore offer a treatment for these disease states.
A member of another subclass of protein kinases, the extracellular-signal-regulated kinase 2, hereinafter referred to as ERK2, is involved in the pathological hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles (NFT) with potential implications in neurodegenerative diseases and specifically in Alzheimer's disease (AD), as shown by Drewes, G. et al., EMBO J., 1992, 11, 2131–2138, and by Roder, H. M. et al., BBRC, 1993, 193, 639–647.
Inhibitors of kinases represent novel therapies for disorders caused by the methabolic processes in which protein kinases are involved. Some potent and selective kinase inhibitors have already been discovered both from natural sources and as results of synthetic efforts. The protein kinase inhibitors known in the prior art have very different structures for example pyrimidines, indolinones, pyridinylimidazoles, aminopurines, flavonoids and glycosylated indolocarbazoles. These protein kinase inhibitors are described for example in Adams, J. L. and Lee, D., Curr. Opin. Drug Disc. Dev., 1999, 2, 96–109, Stover, D. R. et al., Curr. Opin. Drug Disc. Dev., 1999, 2, 274–285, Dumas, J., Exp. Opin. Ther. Pat., 2000, 11, 405–429, and Davies, S. P. et al., Biochem. J., 2000, 351, 95–105.
Furthermore, WO 00/01699 describes protein kinase inhibitors based on an indolocarbazole scaffold which is bisubstituted with a carbacyclic moiety on the nitrogen atoms. It has been reported that these compounds are useful for the treatment of neurodegenerative disorders and cancers. This document also describes N-monosubstituted carbacyclic indolocarbazoles which are used as precursors for the preparation of substituted compounds. Measurements of the biological activity of monosubstituted indolocarbazoles have not been described.
One object of the present invention is to provide novel N-carbacycle monosubstituted indolocarbazoles which are kinase inhibitors. In certain objects, the compounds of the present invention are inhibitors of one or more MAP kinases, CD kinases, GSK-3 kinase or PKC kinase isoforms.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt form thereof.